TargetMITO: A rule-based model for generating highly functional synthetic mitochondrial targeting sequence in yeast

Mitochondria are essential organelles containing their own genomes, encoding a few proteins essential for energy production. Most of the mitochondrial proteins are nucleus-encoded, translated as precursors in the cytoplasm, with a large fraction of these precursors properly addressed by an N-terminal mitochondrial targeting sequence (MTS). These MTS share common features but no consensus sequence can explain their functionality nor the precursors-specific determinants of mitochondrial import. To decipher this mechanism, we created a simple computational model to generate highly functional synthetic MTS while maintaining a tight control on the design parameters. Using the budding yeast, we demonstrated the presence of precursors-specific signatures in addressing artificially nucleus-relocated OXPHOS proteins. We also show the ability of six promising candidate synthetic MTS to address a fluorescent reporter to human mitochondria cells. Our research work confirms the uniqueness of the MTS-passenger protein synergy and takes us one step closer towards improving gene therapy-based treatment of mitochondrial diseases. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/707306v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@ab905forg.highwire.dtl.DTLVardef@19365eforg.highwire.dtl.DTLVardef@956b9org.highwire.dtl.DTLVardef@11cb7cf_HPS_FORMAT_FIGEXP M_FIG C_FIG